Ocular hypertension is the most significant risk factor for glaucoma, and IOP reduction remains the primary goal of glaucoma treatment. The steady state IOP is set by aqueous production and outflow, and it is our knowledge of aqueous dynamics that provides a rational basis for understanding ocular hypertension and the various treatment modalities used to manipulate IOP. The goal of this project is to address a fundamental gap in our knowledge of aqueous dynamics: the role of ciliary blood flow in aqueous production. The project will test the hypothesis that, for a given level of secretory stimulation, aqueous production is blood flow dependent if blood flow falls, and that the known insensitivity of aqueous production to changes in perfusion pressure is due to ciliary blood flow autoregulation (i.e., the maintenance of flow despite changes in perfusion pressure). The project's specific aims are to quantify the interrelationships between ciliary blood flow, metabolism, and aqueous production over a wide range of perfusion pressures under control conditions and after administration of drugs expected to alter aqueous production or ciliary blood flow, or both. The experiments will be performed in anesthetized rabbits instrumented with hydraulic occluders on the inferior vena cava and aorta to control mean arterial pressure (MAP) which will be measured via an arterial cannula. The eye will be cannulated to measure IOP. Ciliary and choroidal blood flow will be measured by laser Doppler flowmetry using fiber optic probes placed on the sclera over the ciliary body and in the vitreous over the posterior pole. Ciliary metabolism will be estimated from ciliary P02, pH and transepithelial potential measurements. Aqueous production will be measured by fluorophotometry. The standard protocol will entail holding the MAP at different levels above and below baseline for 40-60 min to obtain steady state measurements. The protocol will be performed initially in control animals to establish the normal relationships between the measured variables, and then under conditions of drug-induced secretory stimulation and inhibition, and ciliary vasodilation and vasoconstriction. Plotting the aqueous flow as a function of ciliary blood flow will indicate which drugs alter aqueous production directly at the cellular level, those that affect production indirectly due to their vascular effects, and those that affect production directly and indirectly. This information will further our understanding of the physiology underlying aqueous dynamics and the pharmacology of drugs currently used in the treatment of glaucoma, and also be used to continue the development of a comprehensive mathematical model of ocular hydrodynamics.